Melanoma is the most malignant of skin cancers. In the USA, the incidence of melanoma is increasing more rapidly than any other cancer. Melanoma is the most frequently occurring cancer in women from the ages of 25-30, and has recently replaced leukemia as responsible for the most lost work hours in the United States. Currently there is no approved therapy that achieves more that a 20% response rate. Therefore, better therapies for malignant melanoma are urgently needed. Introgen Therapeutics is developing a novel anti-tumor gene therapeutic, Ad-mda7, and in the Phase I STTR research studies conducted in collaboration with University of Texas, M.D. Anderson Cancer Center, has demonstrated it's anti-tumor potential in human melanoma cell lines and animal models of metastatic cancer. Mda7 is a melanocyte-derived tumor suppressor gene, with interleukin properties, and has recently been designated IL-24. In our other studies a preliminary Phase I clinical trial testing has provided initial safety information, as well as preliminary data of immune activation. Here, we propose proof-of-principle experiments to evaluate the biological efficacy of Ad-mda7 in melanoma patients with recurrent in transit disease. This has now led to melanoma patient safety studies, IND filing and subsequent Phase II clinical trial evaluation of Ad-mda7 in the Phase II STTR. The primary aims of this proposal are to conduct the clinical trial with Ad-mda7 (Aim 1), evaluate the patient biological material and responses to establish the biologic efficacy (Aim 2), optimize Ad-mda7 combination therapies in human in vitro models (Aim 3), and assess the possibility of systemic delivery in metastatic mouse melanoma models (Aim 4).